Roundtable Discussion on Musculoskeletal Injury and Trauma

The roundtable on Musculoskeletal Injury and Trauma was organized into three sessions—Basic Science Research; Clinical/Epidemiology Research; and Translational Research/Regenerative Medicine. Throughout the day, participants emphasized that basic researchers, bioengineers, and clinicians must collaborate when developing and testing new therapies.

Musculoskeletal injury and trauma affect multiple tissues—including muscle, bone, skin, connective tissue, and nerves. Basic research focusing on regeneration or repair of just one damaged element (e.g., bone or muscle) is less likely to be translated to the clinic than an integrated approach reflecting an appreciation for interactions among multiple components (e.g., nerves and muscle function; bone, muscle, and connective tissue).

Patient care is another area of musculoskeletal injury and trauma that would benefit from greater collaboration. The ways in which a surgeon might define a successful outcome following traumatic injury differ from successful outcomes as defined by a physical therapist, neurologist, psychologist, patient, or caregiver; such differences are important when evaluating an intervention's utility. Furthermore, due to the complexity of musculoskeletal injury, multiple specialists must be represented in patients' rehabilitation plans if patients are to recover as fully as possible.

Productive collaborations have been developed between non-governmental organizations and the NIAMS and must continue to be pursued. A training program that the NIAMS and the Orthopaedic Research and Education Foundation developed to support training of orthopaedic surgeons who are interested in clinical research or epidemiology (http://grants.nih.gov/grants/guide/pa-files/PAR-06-539.html) was mentioned as another example. And, even if organizations are not willing to make a financial commitment, they help by informing their members about musculoskeletal-related funding opportunities, thereby promoting the submission of promising applications that the NIAMS can then fund. Discussants who knew of organizations that might be interested in supporting musculoskeletal injury and trauma researchers were urged to talk with NIAMS staff.

Discussion

Although much of the afternoon was reserved for discussion of translational research and regenerative medicine, the topics also were mentioned repeatedly during the basic science and clinical/epidemiology sessions.

The orthopaedic community has made incredible advances with respect to getting bone to regenerate-considerably less progress has been made toward regenerating muscle, nerve, and connective tissue. Although muscle can be grown in vitro, the development of innervated, vascularized, functional muscle that can be implanted into a patient is much more challenging. Because multiple tissues form simultaneously during development, participants indicated that researchers who study regeneration should communicate with developmental biologists and researchers who study embryonic stem cells. Pressing issues relevant to human development during gestation and to healing following trauma include unknown factors that cause stem cells to differentiate into certain tissues, positional cues that tell cells to form upper or lower extremities, and signals following injury that promote inflammation and scarring rather than remodeling and regeneration. The role of matrices in stimulating cell growth was noted as another understudied topic.

Engineered tissues, and the substrates on which they are grown, must be capable of withstanding physiologic forces and stresses that engineers at present cannot model in the laboratory. The role of mechanical loading in cell proliferation, differentiation, and apoptosis are other topics that are poorly understood, particularly in the context of rehabilitation following injury or surgery. Participants speculated that orthopaedic trauma researchers who are interested in muscle may benefit from collaborating with members of the muscular dystrophy research community.

Because stem cells are not likely to help patients who were injured decades ago, research continues to be needed to improve the functioning of this patient population (many of whom are likely to live for several more decades with disabilities due to their injuries).

Although regeneration is the "quantum leap" that will change the field of orthopaedic trauma, participants indicated that immunologic research directed toward improving outcomes following transplantation also has considerable potential.

Hand transplantation, ACL repair, blast injury, soft tissue damage following a fracture, and rotator cuff tears were mentioned as examples of conditions for which researchers do not have accurate animal models. NIAMS staff reminded participants that the NIH is developing repositories for transgenic and other animal models, and the National Center for Research Resources supports a large animal resource program. Participants noted that an animal model's utility depends on the skill of the surgeon that is testing a procedure. Development of virtual human models was put forth as a complementary research tool for providing clinically relevant information that would allow investigators to modify variables more efficiently than they can when using live animals.

Improved non-invasive approaches for assessing a procedure's success were thought to be useful for both research and clinical practice. Biomarkers and improved imaging technologies (such as ultrasound or optical tomography) were mentioned as two examples.

Injury and trauma as they manifest in people who are not otherwise healthy adults also were mentioned as deserving further study. The prevention and treatment of trauma due to falls, which are likely to increase as the U.S. population ages, were mentioned as specific topics. Effective interventions to prevent osteoporosis in older adults who require long-term immobilization of injured limbs would have profound public health benefits. Injuries that are infrequent but severely disabling (e.g., humerus fractures) also are understudied.

The needs of pediatric patients, both otherwise healthy children who suffered an injury and those who have a specific disease (e.g., osteogenesis imperfecta, neurofibromatosis) also were mentioned. Researchers need to develop better methods to measure how both the patients and their care givers are affected, and to validate and implement approaches to care that address psychosocial issues associated with caring for a sick or injured child.

Other outcomes research needs identified by participants included a valid approach to evaluate cost in the context of patient preferences and outcomes. Results from such studies would be important not only for clinical practice, but also for policy making. Strategies to better organize and deliver orthopaedic trauma care in a way to treat the entire patient, rather than just the site of orthopaedic injury, also need to be developed; effective team-based therapies to reduce long-term disability would have a huge public health benefit.

Clinical investigators, health services researchers, and health care providers were said to have difficulty making connections between patient-oriented outcomes and clinically relevant endpoints. The perspectives of all three groups must be incorporated into clinical studies if they are going to be integrated into clinical practice.

Like other fields, the musculoskeletal injury and trauma community conducts efficacy studies that may not be applicable to clinical practice or battlefield experience. Some studies fail to have an impact because, in an effort to have a hypothesis that is testable, the study is designed such that clinical implications are unclear. For example, a study designed to meet regulatory requirements (i.e., to answer a question from the FDA) may not use a model that can provide the information relevant to the surgical community. A concerted effort must be made, therefore, to develop studies that can satisfy both sets of demands, as well as to ensure that endpoints relate directly to both the hypothesis and to clinical practice, regardless of whether the findings are positive or negative.

Participants also indicated that clinical investigators studying orthopaedic research questions have trouble randomizing patients; because studies are not blinded, patients drop out if they do not like the treatment option to which they are assigned. Difficulty in obtaining informed consent during acute trauma was mentioned as another obstacle. In summary, the researchers indicated that new study designs and analytic models that provide robust, clinically useful information (but are not randomized, controlled clinical trials) would be useful.

Participants debated briefly about the standards to which clinical investigations should be held. The Congress, on behalf of the American public, frequently asks the NIH to demonstrate how federally funded studies are changing clinical practice. Some were concerned that judging a clinical study by whether it changed medical practice was unreasonable, because basic research investigations are not held to the same standard. Others thought that all studies, whether clinical or basic, should be expected to improve public health.

Clinical studies, like basic experiments, contribute incrementally to the body of knowledge that is implemented by health care providers. The NIAMS-funded Lower Extremity Assessment Project (LEAP) was mentioned as an example of a study that contributed to an overall understanding of how to manage severe injuries. It alone, however, was not sufficient to convince surgeons that people who have amputations do not necessarily fare any better than those with limb-sparing techniques.

When doctors have a history of treating patients successfully with a particular approach, they are reluctant to change their methods. Furthermore, if a study renders a technology or technique obsolete, it generates considerable conflict of interest for those whose livelihoods will be affected.

In an effort to facilitate translation of research findings into clinical practice, clinicians have to be involved in a research question from the beginning. One suggested strategy entailed having professional societies facilitate conversations with their constituents as studies are being developed and conducted. Widely attended panel discussions at annual meetings, for example, would raise awareness of studies and allow the "criticism and countercriticism" discussion to begin and be partially resolved before results are available.

Raising the profile of clinical studies as they are conducted also may increase awareness of clinical research as a profession. At present, clinical research is not generally viewed as a popular career choice due, in part, to a lack of role models and increasingly burdensome regulatory requirements. Orthopaedic surgeons also noted a decrease in the number of fellows who are specializing in trauma. The struggle involved in encouraging clinicians in any field to conduct research, combined with a difficulty in persuading orthopaedic surgeons to specialize in trauma, makes the question of how to increase the number of clinical trauma researchers particularly challenging.

Ongoing discussions of clinical or bioengineering trials also may encourage basic researchers to become involved in translational research. However, participants noted that improved visibility of clinical research does not address the major impediment to engaging basic researchers in such studies-the reward system under which the laboratory researchers function. Because traditional departments are not perceived as rewarding high-risk research, basic scientists who may otherwise be interested in translational and clinical orthopaedic studies are not pursuing them because their professional standing is related to publications in their own fields.

Another impediment to productive collaborations between regenerative medicine researchers and bioengineers is the paradigms to which each group subscribes. When considering new therapies for a patient who has a torn ACL, for example, the bioengineers will develop a tissue or device that will function as an ACL, while the regenerative medicine community will encourage the patient's own ACL to regrow.

Honoring a request made at the beginning of the meeting, participants did not discuss particular activities in which the NIAMS should engage. They repeatedly noted, however, that much of the research that gets funded is the research that people can do, not the research that needs to be done, and asked the NIAMS to consider ways that investigators can get funding to explore difficult but necessary questions, as well as the less ambitious questions for which answers can readily be obtained.

Our Mission

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.